Identification of new 1,2,3-Triazole analogues of sulfanilamide as inhibitors of the carbonic anhydrase II enzyme: Comprehensive in-vitro and in-vivo analyses.

Carbonic anhydrases (CAs) play a vital role in various physiological processes by catalyzing the reversible hydration of CO2 into HCO3-, hence maintaining the fluid and pH balance. Overexpression of carbonic anhydrases II (CA II) is associated with diseases, such as glaucoma, and epilepsy; therefore, it is considered as an important clinical target. Therapeutically used CA inhibitors exhibit several undesirable effects; therefore, there is an urgent need to identify new, safe, and effective inhibitors of the CAs. Keeping in view the importance of CA II inhibition, a library of new 1,3-disubstituted-1,2,3-triazole analogues of sulfanilamide is synthesized via Click chemistry, starting from sulfanilamide azide and different substituted propargyl ethers, incorporating benzyl and heteroarylmethyl moieties. The new derivatives showed significant CA II inhibitory activity (IC50 ranging between 0.19 0.66 μM) when compared with the standard inhibitor, acetazolamide (0.13 ± 0.01 μM). Among all, compounds 16 and 17 showed the most potent activity (IC50 = 0.19 μM) followed by compounds 23, and 18 (IC50 = 0.24 ± 0.014 and 0.26 ± 0.04 μM, respectively). Kinetics studies showed that all compounds are competitive inhibitors of bCA II enzyme (Ki ranging between 0.14-0.68 μM). Additionally, molecular docking studies revealed that all compounds formed network of interactions with the active site residues of the bCA II enzyme. All compounds were found to be non-toxic against BJ Human fibroblast cells. From in-vivo studies, we found that CA activity was significantly inhibited by the intraperitoneal administration of compounds 16 and 17 for up to 5 h. In conclusion, new 1,2,3-triazole analogues of sulfanilamide were identified as good CA II inhibitors.